Abstract 5486: Combining bromodomain and extraterminal (BET) protein inhibitor treatment with standard MAPK inhibitors improved MAPK signaling inhibition in colorectal cancer
Authors: Hey Min Lee, Alexey Sorokin, Preeti Kanikarla Marie, Saikat Chowdhury, Anand Singh, Amanda Anderson, Jumanah Yousef Alshenaifi, Funda Meric-Bernstam, Kunal Rai, Scott Kopetz
Journal: Cancer Research (2023)

Abstract Background: Overexpression and activation of the MAPK signaling pathway is known to play a key role in colorectal cancer (CRC) progression. Substantial efforts have been made to target MAPK signaling pathways in CRC, particularly blocking oncogenic mutations in KRAS or BRAF. However, standard treatments targeting MAPK signaling have demonstrated limited activities in CRC patients and are in strong need of improved efficacies. Thus, we investigated how the combination of BET inhibitor treatment could affect MAPK signaling activation. Methods: We performed a wide-scale drug combination study testing 15 drug combinations using CRC patient-derived xenograft (PDX) models. PDX models were treated for 21 days, and tumor volume and body weight changes were measured for assessment of treatment responses and toxicities. For the BET inhibitor (iBET-151) plus MEK inhibitor (binimetinib or trametinib) combination, RNA-seq and RPPA was performed on PDX tumor tissues collected after 7 days of treatment for pharmacodynamics study (n=3 per treatment condition). Tumors collected on day 21 were sequenced for H3K27Ac ChIP-seq and IHCs for understanding epigenomic changes in active enhancers and target validations. Results: Our preliminary screening of 15 drug combinations in CRC PDX models have shown the most promising and active responses in a combination of BETi with MEKi (5 out of 20 PDXs obtained tumor regression). Preclinical H3K27ac ChIP-seq data has shown lost enhancer peaks after BET inhibition were significantly associated with RAS signaling pathways (q&amp;lt;0.05). Gene set enrichment analysis on preclinical transcriptomic data also demonstrated downregulation of KRAS-signaling in BETi plus MEKi combination treatment compared to MEKi as monotherapy (p&amp;lt;0.05). MAPK activation scores (MPAS) were also significantly downregulated in transcriptomic and enhancer levels under BETi plus MEKi combinations compared to MEKi. Downstream transcription factors of MAPK signaling pathways, such as MYC and FOSL1, were synergistically downregulated in combination with BETi. Also, we found downregulation of EREG, a member of the epidermal growth factor (EGF) family, under BET inhibition which may play a role in MAPK downregulation together with standard therapy. Conclusions: Some studies have shown MAPK signaling activation as a resistance mechanism of BET inhibition in multiple cancer types. However, the understanding of the crosstalk between the activity of BET inhibition in a combination with MAPK signaling inhibition is limited in CRC. We found BET inhibition induces deeper inhibition of MAPK pathway activation together with standard targeted therapies. Our data demonstrated transcriptomic and epigenetic levels of the mechanism of BETi activity together with MAPK inhibition in CRC. Citation Format: Hey Min Lee, Alexey Sorokin, Preeti Kanikarla Marie, Saikat Chowdhury, Anand Singh, Amanda Anderson, Jumanah Yousef Alshenaifi, Funda Meric-Bernstam, Kunal Rai, Scott Kopetz. Combining bromodomain and extraterminal (BET) protein inhibitor treatment with standard MAPK inhibitors improved MAPK signaling inhibition in colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5486.